ANGPTL8 (alternatively called TD26, RIFL, Lipasin, C19orf80 and Betatrophin) is a newly recognized ANGPTL family member that has been implicated in both triglyceride (TG) and glucose metabolism. It is a circulating protein that is expressed primarily in liver and adipose tissue. Unlike ANGPTL3 and ANGPTL4, ANGPTL8 lacks a fibrinogen like domain at the C-terminus, but contains an N-terminal coiled-coil domain, much like other ANGPTL family members. Phylogenetic analysis reveals that ANGPTL8 shares common ancestors with ANGPTL3 and ANGPTL4 (Fu, Z. et. al., (2013), Biochem. Biophys. Res. Commun. 430:1126-1131).
Hepatic overexpression of ANGPTL8 is associated with hypertriglyceridemia, whereas inactivation of Angptl8 causes a reduction in plasma TG levels (Quagliarini, F. et. al. (2012), Proc. Natl. Acad. Sci. USA 109(48):19751-19756; Wang, Y. et. al. (2013), Proc. Natl. Acad. Sci. USA 110:16109-16114). Despite the consensus that ANGPTL8 is involved in lipid regulation, the mechanism responsible for this process is still under debate. One proposed mechanism is that ANGPTL8 inhibits lipoprotein lipase (LPL) activity, resulting in reduced triglyceride hydrolysis and clearance (Zhang, R. et. al., (2012), Biochem. Biophys. Res. Commun. 424:786-792).
ANGPTL8 has also been reported to play a role in beta cell proliferation and beta cell mass in mice, where insulin resistance was induced by an insulin receptor antagonist, S961 (Yi, P. et. al. (2013), Cell 153:747-758). However, subsequent studies revealed that ANGPTL8 is not required for beta cell function, or the beta cell growth response to insulin resistance. Furthermore, overexpression of ANGPTL8 does not increase beta cell area or improve glycemic control (Gusarova, V. et. al. (2014) Cell 159:691-696).
Since hepatic overexpression of ANGPTL8 is associated with hypertriglyceridemia and since inactivation of Angptl8 results in a reduction in plasma triglyceride levels, an inhibitor or antagonist of ANGPTL8 may prove effective in treating a disease characterized in part by elevated levels of triglycerides, such as, but not limited to, hypertriglyceridemia.
Zhang reported that a monoclonal antibody to lipasin, when injected intraperitoneally to wildtype mice, decreased serum triglyceride levels (Zhang, R. (2015), Endocrine Society's 97th Annual Meeting, Presentation No. OR13-6, March 5-8, San Diego, Calif.). However, no fully human antibodies specific for ANGPTL8 have been described to date that may be used in a clinical setting to treat diseases, or conditions characterized by elevated levels of triglycerides, including hypertriglyceridemia.
Accordingly, there is a need in the art for novel antagonists of ANGPTL8, such as the antibodies described herein, for treating patients suffering from hypertriglyceridemia and other disorders or conditions associated with elevated triglyceride and lipid levels.